Increased NonREM sleep time, sleep episode duration, and EEG delta power reflect normal compensatory sleep responses (CSR) to extended wakefulness and constitute a central tenet of sleep physiology- that sleep is homeostatically regulated. In rats, catecholamine releasing stimulants (e.g., methamphetamine) also potently induce CSR. Wakefulness induced by selective dopamine reuptake blockers (e.g., GBR12909), however, produces no CSR, suggesting dopamine transporter involvement in sleep homeostatic mechanisms. To further investigate this possibility we will first confirm that these phenomena generalize to mice. We will then investigate stimulant interactions with sleep homeostasis in mice with null mutations of the dopamine transporter allele and in Cast/Ei mice. Our preliminary data show that Cast/Ei mice have less sleep time and attenuated compensatory sleep responses to sleep deprivation and methamphetamine-induced wakefulness relative to C57BL/6 mice. Using high throughput automated sleep scoring technology, we will investigate the involvement of the dopamine transporter in sleep homeostasis, and will begin to identify the genetic underpinnings of sleep regulatory variation between C57BL/6 and Cast/Ei mice. Four interrelated specific aims will test the hypotheses that: (1) mice (C57BL/6J) exhibit compensatory sleep responses to behavioral SD or methamphetamine-induced wakefulness, but do not exhibit compensatory sleep responses to wakefulness induced by the selective dopamine reuptake blocker GBR12909 or adenosine receptor antagonists, akin to that observed in laboratory rats; (2) the cell membrane dopamine transporter is necessary for the wakefulness-promoting effects of GBR12909, methamphetamine, caffeine and cyclopentyltheophylline.; (3) the cell membrane dopamine transporter is a functional constituent of sleep homeostasis and is therefore necessary for compensatory sleep responses to sleep deprivation (SD). We will also test the hypothesis that (4) three sleep phenotypes that differ between C57BL/6 mice and Cast/Ei mice - i.) total sleep time, ii.) compensatory sleep response to behavioral SD, and iii.) compensatory sleep response to wakefulness induced by methamphetamine treatment-- are not regulated by distinct genetic loci. Finally, we propose a set of pilot studies that will test if the cell membrane serotonin transporter is necessary for compensatory sleep responses to sleep deprivation and wakefulness induced by methamphetamine. The proposed research will advance our understanding of dopaminergic stimulant interactions with sleep homeostasis, CSR mechanisms, and genetic determinants of phenotypic variation in sleep homeostasis.